Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=2)[S:5][CH2:4][CH2:3]1.C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.O[C:39]1[CH:49]=[CH:48][C:42]([C:43]([O:45][CH2:46][CH3:47])=[O:44])=[CH:41][CH:40]=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][C:39]3[CH:49]=[CH:48][C:42]([C:43]([O:45][CH2:46][CH3:47])=[O:44])=[CH:41][CH:40]=3)=[O:13])[CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CC1(C)CCSc2ccc(C(=O)O)cc21
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(OC(=O)c2ccc3c(c2)C(C)(C)CCS3)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 280 mg (1.26 mmol) of 4,4-dimethyl-6-carboxythiochroman and 252 mg (2.52 mmol) of triethylamine in 15 ml of chloroform was stirred at room temperature for 0.5 hours and then treated with 481 mg (1.26 mmol) of bis(2-oxo-3-oxazolidinyl)phosphinic chloride. The reaction mixture was stirred for 0.5h, treated with 209 mg (1.26 mmol) of ethyl 4-hydroxybenzoate and then stirred at room temperature for a further 12 hours. The reaction mixture was washed successively with dilute HCl and saturated sodium bicarbonate solutions The organic layer was concentrated in-vacuo and the resultant crude product purified by flash chromatography (silica; 10% ethyl acetate in hexane) followed by reversed-phase high pressure liquid chromatography (Whatman Partisil M20 10/50 ODS-2; 10% water in acetonitrile) to give the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:20][C:21]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>ClCCl.O>[CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[C:23]([C:22]1[CH:26]=[CH:27][CH:28]=[C:29]([CH3:30])[C:21]=1[CH3:20])=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(C(=O)Cl)c1C
Reactant: c1ccc(Cn2ccnc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cccc(C(=O)c2nccn2Cc2ccccc2)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.3 %

Procedure:
To a solution of 1-benzyl-1H-imidazole (1.69 Kg, 10.56 mol) in dichloromethane (14.0 L), at −7° C., was added triethylamine (1.61 kg, 10.56 mol). A solution of 2,3-dimethylbenzoyl chloride (2.0 kg, 11.99 mol) in dichloromethane (6.0 L) was then added drop wise and the reaction mixture was stirred at room temperature for 16 h. The reaction was monitored by Thin layer Chromatography. After completion of the reaction, the reaction mixture was diluted with water (5.0 L) and the mixture was stirred for a further 15 min. The two layers were separated and the organic phase was concentrated in vacuo. To the residue was added toluene (8.0 L) and the solution was cooled to −5° C., before addition of hydrochloric acid (5N, 8.0 L). The two layers were separated and the aqueous layer was adjusted to pH 9-12, by addition of aqueous sodium hydroxide solution (50%), and extracted with toluene (4.0 L and then 8.0 L). The combined organic phases were concentrated in vacuo to give the title compound (2.8 kg).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[OH:12].[Na+].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl>[CH3:1][C:2]1[C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=[CH:4][N+:3]=1[O-:12]
Reactant: Cc1nccc2c1OCO2
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c2c(cc[n+]1[O-])OCO2

Procedure:
To the methylene chloride solution of 2-methyl-3,4-methylenedioxypyridine from example I 21 sodium hydrogen carbonate (1M, 50 ml) and MCPBA (4 g, 70%) were added. The mixture was stirred at ambient temperature for 15 min whereupon the excess of MCPBA was destroyed with addition of sodium thiosulphate (1 g). The organic phase was separated and the aqueous phase was extracted with methylene chloride (3×50 ml). The collected organic phases were concentrated under reduced pressure and chromatographed on silica (CH2Cl2 /MeOH, 90:10). Yield: 120 mg (7,8%) of the title compound.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])([O-])=O.[F:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[F:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:4]2[CH:5]=[C:6]([CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=2)[C:7]([O:9][CH3:10])=[O:8])=[CH:20][CH:19]=1
Reactant: Oc1ccc(F)cc1
Reactant: COC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Oc2ccc(F)cc2)cc([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
The compound prepared in Example 34 (4.73 g) was dissolved in DMF (40 mL), added with 4-fluorophenol (2.34 g) and potassium phosphate (5.32 g) and stirred overnight at 80° C. The reaction solution was diluted with ethyl acetate, sequentially washed with water and a saturated sodium chloride solution and dried over anhydrous magnesium sulphate before distillation of the solvent. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=9:1→1:1) to give the titled compound (4.81 g) having the following physical properties.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4](=O)[CH2:5][C:6](=O)[CH2:7][CH2:8][CH3:9].CO.[C:14]([CH2:16][C:17]([NH2:19])=[O:18])#[N:15].C[O-].[Na+]>O.C(O)(=O)C>[C:14]([C:16]1[C:17](=[O:18])[NH:19][C:6]([CH2:7][CH2:8][CH3:9])=[CH:5][C:4]=1[CH2:3][CH2:2][CH3:1])#[N:15]
Reactant: N#CCC(N)=O
Reactant: CCCC(=O)CC(=O)CCC
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CCCc1cc(CCC)c(C#N)c(=O)[nH]1
Reaction time: 22 h
Yield: 81.9 %

Procedure:
3-Cyano-4,6-di-n-propyl-2(1H)-pyridinone was prepared as follows: A mixture containing 15.6 g of 4,6-nonanedione, 200 ml of methanol, 10 g of cyanoacetamide and 6 g of sodium methoxide was refluxed with stirring for 22 hours and then stripped to dryness in vacuo. The residue was dissolved in 100 ml of water and the solution acidified with acetic acid. The white precipitate was collected, washed with water, air-dried, recrystallized from isopropyl alcohol-n-hexane and dried in vacuo at 80°-85° C. to produce 16.7 g of 3-cyano-4,6-di-n-propyl-2(1H)-pyridinone, m.p. 151°-152° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:19][CH3:20])=[C:13]([CH:18]=1)[C:14](=[O:17])[CH2:15]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1.[H-].[Na+].O>CN(C)C=O>[N:24]1[CH:25]=[CH:26][CH:27]=[C:22]([O:21][CH2:15][C:14]([C:13]2[CH:18]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=[CH:11][C:12]=2[O:19][CH3:20])=[O:17])[CH:23]=1
Reactant: COc1ccc(OCc2ccccc2)cc1C(=O)CBr
Reactant: Oc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(OCc2ccccc2)cc1C(=O)COc1cccnc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 25.7 %

Procedure:
To 5-benzyloxy-2-methoxyphenacyl bromide (4.0 g, 0.0119 mol) in 80 ml of dry dimethylformamide was added 3-hydroxypyridine (1.24 g, 0.013 mol, 1.1 equiv) followed by NaH (50% in oil, 0.604 g, 1.1 equiv). After stirring for 18 hours under N2, the mixture was poured into 500 ml of ice and water, and extracted 2×500 ml ethyl acetate. The organic layers were combined, washed 2×500 ml H2O and 1×300 ml brine, dried (Na2SO4), stripped to an oil, and chromatographed on silica gel using 1:1 hexane:ethyl acetate as eluant to yield 1.07 g of present title product as a solid; IR(KBr) 1670 cm-1;MS 349 (M+); 1H-NMR (300 MHz, CDCl3) delta (ppm) 3.95 (s, 3H), 5.1 (s, 2H), 5.35 (s, 2H), 2.0 (d, 1 H), 7.2-7.5 (m, 8H), 7.6 (d, 1H), 8.3 (d, 1H), 8.4 (d, 1H).
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:13][N:14]([CH3:24])[CH2:15][CH2:16][N:17]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[C:1]([N:20]1[CH2:21][CH2:22][CH2:23][N:17]([CH2:16][CH2:15][N:14]([CH3:24])[CH3:13])[CH2:18][CH2:19]1)(=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CN(C)CCN1CCCNCC1
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)N1CCCN(CCN(C)C)CC1

Procedure:
The same procedures as in Example 2 were carried out using (E)-2-decenoic acid and 1-(2-dimethylaminoethyl)-1,4-diazepane as starting raw materials, to produce an intended compound.
Reaction SMILES: FC(F)(F)C([N:5]([C@@H:13]1[CH2:15][C@H:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=O.[CH:24]([C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([OH:35])=[O:34])=[CH:28][CH:27]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl>[C:16]1([C@@H:14]2[CH2:15][C@H:13]2[NH:5][CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([CH2:24][C:26]3[CH:27]=[CH:28][C:29]([CH2:32][C:33]([OH:35])=[O:34])=[CH:30][CH:31]=3)[CH2:11][CH2:12]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=Cc1ccc(CC(=O)O)cc1
Reactant: O=C(N(CC1CCNCC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: O=C(O)Cc1ccc(CN2CCC(CN[C@@H]3C[C@H]3c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.8 %

Procedure:
To a solution of 2,2,2-trifluoro-N-((1R,2S)-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (120 mg, 0.368 mmol) in 1,2-dichloroethane (DCE) (2 mL) were added 2-(4-formylphenyl)acetic acid (72.4 mg, 0.441 mmol) and sodium triacetoxyborohydride (125 mg, 0.588 mmol), and the reaction mixture was stirred at room temperature for 18 h. The mixture was quenched with water (2 mL) and extracted with DCM (3×). The extract was dried (Na2SO4) and concentrated. The residue was dissolved in methanol (2.000 mL) and sodium hydroxide (1M, 2 mL, 2.000 mmol) was added. The mixture was stirred at room temperature for 3 h and concentrated. The residue was treated with methanol and filtered. The filtrate was purified using reverse-phase HPLC under the acidic conditions. The fractions containing product were combined, treated and concentrated. The residue was further dried under vacuum to give 54 mg of product (HCl salt) as off-white solid. MS: (M+H)+=379.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20-1.34 (m, 1H), 1.51-1.70 (m, 3H), 1.87-2.13 (m, 3H), 2.56-2.66 (m, 1H), 2.83-3.15 (m, 5H), 3.32 (br. s., 2H), 4.16-4.44 (m, 2H), 7.12-7.43 (m, 7H), 7.45-7.61 (m, 2H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([CH2:14][NH:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[S:17])=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1.[CH2:25](Br)[CH:26]=[CH2:27]>O1CCCC1>[CH2:27]([S:17][C:16](=[N:15][CH2:14][C:5]1[C:4]([Cl:3])=[CH:9][C:8]([C:10]([F:13])([F:12])[F:11])=[CH:7][N:6]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[CH:26]=[CH2:25]
Reactant: FC(F)(F)c1cnc(CNC(=S)c2ccccc2Cl)c(Cl)c1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCSC(=NCc1ncc(C(F)(F)F)cc1Cl)c1ccccc1Cl
Reaction time: 0.33 h

Procedure:
To a mixture of sodium hydride (0.33 g) in tetrahydrofuran (10 ml) was added N-[(3-chloro-5-trifluoromethyl-2-pyridyl)methyl]-2-chlorobenzenethioamide (for preparation see PCT/GB/99/00304) (3.07 g) in tetrahydrofuran (50 ml) dropwise with stirring for 20 minutes until effervescence had ceased. Allyl bromide (0.09 g) in tetrahydrofuran (5 ml) was added to the reaction mixture, and the solution was stirred overnight at room temperature. The mixture was evaporated to dryness and the residue partitioned between dichloromethane (10 ml), water (5 ml) and brine (5 ml). The organic phase was separated and the solvent and any residual water evaporated in vacuo. The residue was purified by silica gel chromatography, gradient eluting with light petroleum (b.p. 60-80° C.)/diethyl ether to give the title product.
Reaction SMILES: COC(C1C=C(OC2C=CC(S(C)(=O)=O)=CC=2)C=C2OC(C)CC=12)=O.[F:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1F)[C:30]#[N:31].[CH3:36][N:37]1[CH:41]=[CH:40][C:39]([NH:42][C:43]([C:45]2[CH:55]=[C:54]([OH:56])[C:48]3[CH2:49][C:50]([CH3:53])([CH3:52])[O:51][C:47]=3[CH:46]=2)=[O:44])=[N:38]1>>[CH3:36][N:37]1[CH:41]=[CH:40][C:39]([NH:42][C:43]([C:45]2[CH:55]=[C:54]([O:56][C:34]3[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][C:27]=3[F:26])[C:48]3[CH2:49][C:50]([CH3:53])([CH3:52])[O:51][C:47]=3[CH:46]=2)=[O:44])=[N:38]1
Reactant: Cn1ccc(NC(=O)c2cc(O)c3c(c2)OC(C)(C)C3)n1
Reactant: N#Cc1ccc(F)c(F)c1
Agent: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2c1CC(C)O2
Product: Cn1ccc(NC(=O)c2cc(Oc3ccc(C#N)cc3F)c3c(c2)OC(C)(C)C3)n1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 1f, from 3,4-difluorobenzonitrile (11 mg, 0.080 mmol) and 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid(1-methyl-1H-pyrazol-3-yl)-amide (31a) (23 mg, 0.080 mmol) to give a colorless oil (8 mg, 20% yield). 1H NMR (400 MHz, CDCl3) δ 8.49 (s, 1 H) 7.50 (dd, J=10.11, 1.77 Hz, 1 H) 7.42 (d, J=8.59 Hz, 1 H) 7.28 (d, J=2.02 Hz, 1 H) 7.00-7.08 (m, 2 H) 6.95 (s, 1 H) 6.77 (d, J=1.77 Hz, 1 H) 3.78 (s, 3 H) 2.97 (s, 2 H) 1.51 (s, 6 H); LCMS for C22H19FN4O3 m/z (M+H)+407.10.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1.[CH3:12][CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:23])[CH3:22])[C:16]=1[N:24]=[C:25]=[O:26])[CH3:14]>C(OCC)(=O)C>[CH3:14][CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:22])[CH3:23])[C:16]=1[NH:24][C:25]([NH:1][CH:2]1[CH2:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1)=[O:26])[CH3:12]
Reactant: NC1COc2ccccc2C1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Solvent: CCOC(C)=O
Product: CC(C)c1cccc(C(C)C)c1NC(=O)NC1COc2ccccc2C1
Temperature: 25 °C
Yield: 59.1 %

Procedure:
To a solution of 3,4-dihydro-3-amino-2H-benzopyran (0.9 g, 6 mmole) in 50 ml of ethyl acetate, there was added 1.22 g (6 mmol) of 2,6-bis(1-methylethyl)phenyl isocyanate. The resulting mixture was stirred at room temperature for twenty hours. The solvent was removed under vacuum and the residue was suspended in 20% ethyl acetate/hexane. The precipitated solid was collected by filtration and dried to yield 1.25 g of N-[2,6-bis(1-methylethyl)phenyl]-N'-(3,4-dihydro-2H-1-benzopyran-3-yl)urea, mp 186°-188° C.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:20][CH2:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[C:5]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])(=[O:11])=[O:10])=[N:6][CH:7]=1.[CH3:28][N:29](C)C=O>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C-]#N.[Zn+2].[C-]#N>[Cl:19][C:13]1[C:14]([Cl:18])=[CH:15][CH:16]=[CH:17][C:12]=1[S:9]([NH:8][C:5]1[C:4]([O:20][CH2:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[N:3][C:2]([C:28]#[N:29])=[CH:7][N:6]=1)(=[O:11])=[O:10]
Reactant: O=S(=O)(Nc1ncc(Br)nc1OCc1cccnc1)c1cccc(Cl)c1Cl
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: N#Cc1cnc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(OCc2cccnc2)n1
Reaction time: 5 h

Procedure:
N-[5-Bromo-3-(3-pyridinylmethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide (Example 34) (0.15 g), tetrakis(triphenylphosphine)palladium(0) (0.04 g) and zinc cyanide (0.03 g) in N,N-dimethylformamide (5.0 mL) was heated at 70° C. After 5 h, the mixture was diluted with ethyl acetate (30 mL) and washed with 5% aqueous citric acid (5 mL), dried (MgSO4) and evaporated. Chromatography on silica gel eluting with ethyl acetate/isohexane mixtures containing 1% acetic acid gave the title compound as a white solid (0.058 g).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6]1[S:7][CH2:8][C:9](=[O:11])[N:10]=1.[N:17]1[C:26]2[C:21](=[N:22][C:23]([CH:27]=O)=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6]1[S:7][C:8](=[CH:27][C:23]2[CH:24]=[CH:25][C:26]3[C:21](=[CH:20][CH:19]=[CH:18][N:17]=3)[N:22]=2)[C:9](=[O:11])[N:10]=1
Reactant: O=Cc1ccc2ncccc2n1
Reactant: O=C1CSC(NCc2ccc(F)cc2Cl)=N1
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: O=C1N=C(NCc2ccc(F)cc2Cl)SC1=Cc1ccc2ncccc2n1
Temperature: 130 °C
Yield: 47.8 %

Procedure:
To a suspension of 2-(2-chloro-4-fluoro-benzylamino)-thiazol-4-one (41.4 mg, 0.16 mmol), and 1,5-naphthyridine-6-carboxaldehyde (31.6 mg, 0.2 mmol) in toluene (1 mL) in a microwave tube were added benzoic acid (2.0 mg, 0.02 mmol) and piperidine (1.7 uM, 0.02 mmol). The reaction mixture was heated to 130° C. with microwave for 15 min., then cooled to r.t. and diluted with toluene. The solid was collected by filtration and washed with toluene, MeOH and ether to give 2-(2-chloro-4-fluoro-benzylamino)-5-[1,5]naphthyridin-2-ylmethylene-thiazol-4-one as a brown solid (30.5 mg, 47.8%). HR-ES (+) m/e calcd. for C19H12FClN4OS: (M+H)+ 399.0477. Found: 399.0476.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:14]([O-])=O)=[C:7]([CH:13]=1)[O:8][CH2:9][C@H:10]1[CH2:12][O:11]1.C(N(C(C)C)C(C)C)C.[C:26](OC(=O)C)(=[O:28])[CH3:27]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:14][C:26](=[O:28])[CH3:27])=[C:7]([O:8][CH2:9][C@H:10]2[CH2:12][O:11]2)[CH:13]=1.[OH:11][CH:10]([CH3:12])[CH2:9][O:8][C:7]1[CH:13]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[NH:14][C:26](=[O:28])[CH3:27]
Reactant: COc1ccc([N+](=O)[O-])c(OC[C@H]2CO2)c1
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1ccc(NC(C)=O)c(OCC(C)O)c1
Product: COc1ccc(NC(C)=O)c(OC[C@H]2CO2)c1
Reaction time: 0.67 h

Procedure:
A mixture of (2R)-2-[(5-methoxy-2-nitrophenoxy)methyl]oxirane (620 mg, 2.75 mmol), Pd/C (10%, 250 mg), N-ethyl-N-isopropylpropan-2-amine (0.94 mL, 5.5 mmol) and acetic anhydride (0.52 mL, 5.5 mmol) in ethyl acetate (25 mL) was hydrogenated at atmospheric pressure at room temperature for 40 minutes. The catalyst was filtered off and the filtrate was concentrated in vacuo. The residue was purified by silica gel flash chromatography (0-60% ethyl acetate in petroleum spirit) to give sub-title compound (155 mg) and 204 mg of N-[2-(2-hydroxypropoxy)-4-methoxyphenyl]acetamide (see example 14). 1H-NMR (CDCl3, 400 MHz): δ 8.22 (d, J=8.8 Hz, 1H); 7.64 (br.s, 1H); 6.55-6.49 (m, 2H); 4.34 (dd, J=2.5, 11.3 Hz, 1H); 3.94 (dd, J=6.1, 11.3 Hz, 1H); 3.78 (s, 3H); 3.39 (m, 1H); 2.96 (t, J=4.5 Hz, 1H); 2.78 (dd; J=2.6, 4.8 Hz, 1H); 2.20 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[C:13]([CH3:16])[N:14]=[CH:15][C:10]=2[CH2:9]1)=O)(C)(C)C.[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22]>ClCCl>[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22].[CH3:16][C:13]1[N:14]=[CH:15][C:10]2[CH2:9][NH:8][CH2:18][CH2:17][C:11]=2[N:12]=1
Reactant: Cc1ncc2c(n1)CCN(C(=O)OC(C)(C)C)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ncc2c(n1)CCNC2

Procedure:
Reaction of the product from Step A above with trifluoroacetic acid in dichloromethane according to the procedure outlined for Intermediate 28, Step C afforded the title compound as a light orange powder. LC/MS 150.1 (M+1).
Reaction SMILES: N1C2C(=CC=C(C(O)=O)C=2)C=[CH:2]1.C1(=O)CCCCC1.[C:20]1([C:26]2[C:34]3[C:29](=[CH:30][C:31]([C:35]([OH:37])=[O:36])=[CH:32][CH:33]=3)[NH:28][CH:27]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]=1>>[CH:20]1([C:26]2[C:34]3[C:29](=[CH:30][C:31]([C:35]([O:37][CH3:2])=[O:36])=[CH:32][CH:33]=3)[NH:28][CH:27]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: O=C(O)c1ccc2c(C3=CCCCC3)c[nH]c2c1
Solvent: O=C1CCCCC1
Product: COC(=O)c1ccc2c(C3CCCCC3)c[nH]c2c1

Procedure:
Condensation of 1H-indole-6-carboxylic acid with cyclohexanone can generate 3-cyclohexenyl-1H-indole-6-carboxylic acid. This indole ester can be subjected to sequential reduction and esterification to provide methyl 3-cyclohexanyl-1H-indole-6-carboxylate.
Reaction SMILES: [NH2:1][C:2]([CH2:7][OH:8])([CH2:5][OH:6])[CH2:3][OH:4].[Cl:9][C:10]1[C:14]([Cl:15])=[C:13]([CH3:16])[NH:12][C:11]=1[C:17]([NH:19][C@@H:20]1[CH2:25][CH2:24][N:23]([C:26]2[S:27][C:28]([C:31]([OH:33])=[O:32])=[CH:29][N:30]=2)[CH2:22][C@@H:21]1[F:34])=[O:18].CO>O>[Cl:9][C:10]1[C:14]([Cl:15])=[C:13]([CH3:16])[NH:12][C:11]=1[C:17]([NH:19][C@@H:20]1[CH2:25][CH2:24][N:23]([C:26]2[S:27][C:28]([C:31]([O-:33])=[O:32])=[CH:29][N:30]=2)[CH2:22][C@@H:21]1[F:34])=[O:18].[OH:4][CH2:3][C:2]([CH2:7][OH:8])([NH3+:1])[CH2:5][OH:6]
Reactant: NC(CO)(CO)CO
Reactant: Cc1[nH]c(C(=O)N[C@@H]2CCN(c3ncc(C(=O)O)s3)C[C@@H]2F)c(Cl)c1Cl
Solvent: CO
Solvent: O
Product: Cc1[nH]c(C(=O)N[C@@H]2CCN(c3ncc(C(=O)[O-])s3)C[C@@H]2F)c(Cl)c1Cl
Product: [NH3+]C(CO)(CO)CO
Temperature: 60 °C
Reaction time: 8 h
Yield: 32.8 %

Procedure:
Tromethamine (43 mg, 0.36 mmol), 2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-fluoropiperidin-1-yl)-1,3-thiazole-5-carboxylic acid (Example 42, 150 mg, 0.36 mmol), methanol (50 ml) and water (5 ml) were combined and stirred at 60° C. until the mixture was a homogeneous solution (30 min). The mixture was cooled to room temperature and concentrated under reduced pressure. The crude salt (80 mg) was dissolved in ethyl acetate/methanol (8 ml; 50:50) and ethyl acetate was added slowly to the stirred solution until it became cloudy. Stirring was continued and additional ethyl acetate (˜15 ml) was added slowly to the mixture. The mixture was stored at 4° C. overnight. The solid was collected by filtration and air dried for 24 h to provide the salt (64 mg).
Reaction SMILES: C(Cl)(Cl)Cl.Cl.[CH3:6][N:7]1[CH2:15][CH2:14][CH2:13][CH:9]([C:10]([OH:12])=O)[CH2:8]1.ClC(OCC(C)C)=O.[CH:24]1([CH2:32][NH2:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>C(N(CC)CC)C>[CH3:6][N:7]1[CH2:15][CH2:14][CH2:13][CH:9]([C:10]([NH:33][CH2:32][CH:24]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:12])[CH2:8]1
Reactant: CN1CCCC(C(=O)O)C1
Reactant: NCC1CCCCCCC1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN1CCCC(C(=O)NCC2CCCCCCC2)C1
Yield: 62 %

Procedure:
To 80 ml of chloroform were added 3.59 g of 1-methylnipecotic acid hydrochloride and 6.26 ml of triethylamine. Thereto was added 3.0 g of isobutyl chloroformate under ice cooling and stirring. The mixture was stirred for 30 minutes. Thereto was added 3.1 g of cyclooctylmethylamine, and the mixture was subjected to a reaction for 2 hours at room temperature. The reaction mixture was washed with an aqueous sodium hydrogen carbonate solution and with water, and dried with anhydrous sodium sulfate. The solvent was removed by evaporation. The residue was purified by a Silica gel column chromatography (dichloromethane:methanol=10:1) to obtain 3.3 g of 1-methyl-3-cyclooctylmethylaminocarbonylpiperidine.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][OH:6])[CH3:2].[I:9]C.[CH3:11][C:12](C)=O>>[I-:9].[CH2:1]([N+:3]([CH2:11][CH3:12])([CH2:7][CH3:8])[CH2:4][CH2:5][OH:6])[CH3:2]
Reactant: CCN(CC)CCO
Reactant: CI
Reactant: CC(C)=O
Product: CC[N+](CC)(CC)CCO
Product: [I-]
Reaction time: 24 h
Yield: 94.1 %

Procedure:
To 200 g of acetone, 117 g of N,N-diethylethanolamine and 116 g of iodomethane were dissolved. The solution was left for one day. The precipitated white solid was filtered off, and dispersed in 200 g of acetone again. The dispersion was filtered off, and dried to obtain 210 g of N,N,N-triethyl-N-(2-hydroxyethyl)ammonium iodide.